The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, septic shock and multiple organ dysfunction syndrome. The mechanisms that lead to the development of septic shock are not fully understood. For this reason the mortality rate remains unacceptably high, i.e. 28.6%. The macrophage class a scavenger receptor (SRA) is best known for its role in the uptake of modified low density lipoprotein, accumulation of cholesteryl esters in macrophages and its role in atherogenesis. However, recent evidence has demonstrated a role for SRA as an innate immune receptor. We have discovered that SRA also plays a central role in the pathogenesis of septic shock. Specifically, SRA enhances the morbidity and mortality of septic shock. This is a new and novel role for SRA in the pathogenesis of septic disease. The mechanisms by which SRA mediates septic shock involves amplification of the pro-inflammatory, pro-death phenotype associated with septic shock. In addition, SRA facilitates septic sequelae by constitutively inhibiting the TRIF/IRF?/IFN? pro-survival signaling pathway. In addition to these important basic science observations, our studies have also suggested new and novel approaches for the treatment and management of septic shock. We hypothesize that: i) SRA plays a pivotal role in the pathophysiology of septic shock by amplifying the pro-inflammatory, pro-death phenotype associated with septic shock; ii) SRA is an endogenous inhibitor of the TRIF/IRF?/IFN? pro- survival signaling pathway and iii) Modulation of SRA activity and/or administration of exogenous IFN? will be useful in the management and prevention of sepsis/septic shock. We will critically evaluate these hypotheses with the following specific Aims. 1. Delineate the mechanisms by which SRA enhances the pro-inflammatory response to sepsis/septic shock. 2. Define the mechanisms by which SRA inhibits the TRIF/IRF?/IFN? signaling pathway. 3. Determine whether transient antagonism of SRA and/or administration of exogenous IFN? will ameliorate septic sequelae and improve survival outcome in septic shock. A successful completion of this research will result in a new understanding of the cellular and molecular mechanisms of sepsis and may also identify new and novel approaches for the prevention and treatment of sepsis/septic shock. PUBLIC HEALTH RELEVANCE: Sepsis, septic shock and multi-organ failure are major clinical problems in the United States. Despite years of intensive research, there is still much that we do not know about the mechanisms of these devastating diseases. Attempts at developing effective therapies for sepsis/septic shock and multi-organ failture have proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and mechanisms that mediate septic injury. We have made the novel observation that the macrophage class a scavenger receptor (SRA) plays a key role in mediating the morbidity and mortality of sepsis/septic shock. To the best of our knowledge, this is a new and novel role for SRA in disease. Of greater significance, our studies with SR-A have suggested new, and heretofore unanticipated, approaches to the management and treatment of sepsis/septic shock in the critically ill host. At the completion of this research we will have gained a new understanding of the mechanisms of sepsis and we may identify new and novel approaches for the treatment of sepsis/septic shock.